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Acid-sensing ion channels (ASICs) are sodium selective channels that belong to the ENac/DEG family of ion channels. They are sensitive to changes in extracellular pH and are expressed in both the central and peripheral nervous system. There are multiple ASIC subtypes that are involved in different pathophysiological conditions, including neurodegeneration, and most recently, epilepsy. Crystal structure of chicken ASIC1 revealed that functional ASIC is a trimer with large extracellular domain that can interact with variety of ligands, and the focus of research has been to identify ASIC antagonists. The ASIC3 channel subtype is primarily expressed in DRG neurons and is involved in pain sensation, but may activate GABAergic interneurons. ASIC3 is modulated by nonproton ligands like 2-guanidine-4-methylquinazoline (GMQ) and agmatine. We have identified a guanidine compound with a different molecule structure than GMQ that allosterically modulates ASIC3. Here we characterize this guanidine ligand using whole-cell patch clamp electrophysiology and ASIC3 transfected CHO-K1 cells. We found that the ligand is able to activate ASIC3 channel at physiological pH of 7.4, similar to GMQ. Furthermore, the guanidine ligand alters low pH current and delays desensitization, indicating that the ligand may be an ASIC3 positive allosteric modulator. The activation by the guanidine ligand was found to be concentration dependent In the future, we will determine the effect of the guanidine ligand on the ASIC3 window current and identify potential binding sites within ASIC3.

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Poster

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Acid-sensing ion channels (ASICs) are sodium selective channels that belong to the ENac/DEG family of ion channels. They are sensitive to changes in extracellular pH and are expressed in both the central and peripheral nervous system. There are multiple ASIC subtypes that are involved in different pathophysiological conditions, including neurodegeneration, and most recently, epilepsy. Crystal structure of chicken ASIC1 revealed that functional ASIC is a trimer with large extracellular domain that can interact with variety of ligands, and the focus of research has been to identify ASIC antagonists. The ASIC3 channel subtype is primarily expressed in DRG neurons and is involved in pain sensation, but may activate GABAergic interneurons. ASIC3 is modulated by nonproton ligands like 2-guanidine-4-methylquinazoline (GMQ) and agmatine. We have identified a guanidine compound with a different molecule structure than GMQ that allosterically modulates ASIC3. Here we characterize this guanidine ligand using whole-cell patch clamp electrophysiology and ASIC3 transfected CHO-K1 cells. We found that the ligand is able to activate ASIC3 channel at physiological pH of 7.4, similar to GMQ. Furthermore, the guanidine ligand alters low pH current and delays desensitization, indicating that the ligand may be an ASIC3 positive allosteric modulator. The activation by the guanidine ligand was found to be concentration dependent In the future, we will determine the effect of the guanidine ligand on the ASIC3 window current and identify potential binding sites within ASIC3.